Øystein Fluge, Kari Sørland, Ingrid Gurvin Rekeland, Olav Mella
From the year 2014 to 2017 the largest drug trial to date in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) was performed at five Norwegian hospitals – in Bergen, Oslo, Notodden, Trondheim and Tromsø.
The «RituxME» trial included 151 participants who were given a 12 month treatment regime with either the antibody rituximab or saline. The study was funded by the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, the Norwegian Ministry of Health and Care Services, the Kavli Trust and the legacy of Torstein Hereid. The study results are published today in the highly ranked Annals of Internal Medicine
The RituxME trial followed two smaller studies from the Haukeland University Hospital, which showed promising results of treatment with rituximab, which eliminates B-cells from the immune system, in patients with ME/CFS. These studies included a smaller number of patients and had methodical weaknesses, and a new and more comprehensive trial was required in order to confirm or disprove a therapeutic effect of rituximab in ME/CFS.
Randomised and double-blind
The RituxME trial was randomised and double-blind. This means that each participant was randomly allocated to either the rituximab or placebo group, and the patients, researchers, treating physicians and nurses were unaware of which patients received which treatments.
The placebo drug consisted of saline with a small added dose of albumin. Albumin is a protein that created tiny bubbles in the saline, in order to match the visual appearance of the study drug. When the patients were asked after 6 weeks which drug they believed they had received, only 19 of the 151 guessed correctly. Most patients answered that they were not sure which group they had been allocated to.
Professor Øystein Fluge leads the research group for ME/CFS at the Haukeland University Hospital, alongside professor Olav Mella.
Study procedures
In order to qualify for the trial, potential participants must fulfil the Canadian consensus criteria, which are strict diagnostic criteria for ME/CFS. The participants were between 18 and 65 years of age, and suffered from mild to severe degree of ME/CFS. Very severely ill patients, who were bedbound and needed assistance to cover even basic needs, were not eligible for inclusion. The mean age of the 151 participants was 37 years, and at the time of inclusion, they had been ill for anywhere between two and fifteen years – eight years on average. Eighty-two per cent of the study patients were women.
The patients received six treatments over the course of twelve months, followed by another twelve months follow-up. Blood samples were done regularly, and the patients made a considerable effort completing self-report forms assessing their own symptoms every two weeks throughout the study. The participants were also required to wear an activity bracelet measuring number of steps and physical activity level during one week before treatment start and again after 18 months. Only two patients withdrew from the trial during the two-year study period.
*Figure reprint with permission from Annals of Internal Medicine
No effect of rituximab
Analyses of the patient data show that on average, patients in the two groups follow an almost identical course throughout the study.
• 46 patients (30.5%) reported slight to moderate, moderate or major symptom improvement during at least 8 consecutive weeks, which was the pre-defined criterion for clinical improvement.
• 26 of these patients turned out to be in the placebo group, and 20 had received rituximab.
The figure above shows self-reported «fatigue score» (panel A) and physical function based on the Short Form-36 questionnaire (panel B) throughout the trial, for patients in the rituximab and placebo groups.
Panel C shows physical function for patients with unchanged symptom status (60%), patients who reported improvement of varying duration (30%), and patients whose symptoms worsened (10%) during the trial. Patients who had received rituximab and placebo were distributed equally in all groups.
The self-reported data are supported by results from activity measurements and medical consultations, and there is little doubt they represent a true picture of the patients’ clinical course throughout the trial.
We therefore conclude that the trial shows no effect of rituximab in patients with ME/CFS. Furthermore, we have not been able to identify any subgroup of patients who seem to benefit from rituximab treatment.
What do these results mean?
The study provides valuable information on the symptom course of ME/CFS patients during two years close follow-up in a clinical trial. A subgroup of patients experienced symptom improvement during the observation period. It is difficult to say whether this is the natural course of the disease, or whether other mechanisms such as placebo effects due to high expectations, come into play.
The temporary removal of B-cells with rituximab does not seem to have a beneficial effect on the symptoms. This weakens the hypothesis that B-cells could be key to the biological mechanisms behind the disease. However, the results do not rule out the involvement of the immune system in ME/CFS.
International research supports the concept that changes in the immune system play an important role in ME/CFS. There are several examples of randomised trials with rituximab coming up with negative results, even for established autoimmune diseases. It is still possible that other medications, which affect the immune system through other mechanisms of action, could have a beneficial effect on the ME/CFS symptoms.
The sound methodology of the RituxME trial is recognized in a separate editorial in Annals of Internal Medicine, and we believe the trial offers a clear answer to its research question. This is important, and the trial results can help adjust the course for future research into symptom mechanisms, as well as efforts to develop rational therapeutic treatments.
Moreover, the study highlights the importance of performing larger, placebo-controlled trials with double-blind design before drawing firm conclusions. This may be particularly significant in conditions that have no specific biomarkers thus far, and where researchers must rely on self-reported data in order to assess symptom development. Sound methodology and study design are equally important in trials of drug interventions and studies involving other approaches, such as cognitive therapy.
Although side effects were reported by patients who received both the study medication and placebo, the participants generally tolerated the medication well. Many symptoms that were reported as possible side effects, could also be interpreted as fluctuations in the ME/CFS symptoms. Among the 15 patients who reported a general worsening of their symptoms over time, more patients had received placebo than rituximab.
Further research – supported by the Kavli Trust
All trial participants donated blood samples for research purposes before and during the study. These blood samples are stored in a valuable research biobank and are the subject of further studies on the mechanisms behind ME/CFS. Laboratory analyses have already yielded interesting findings, and the Kavli Trust supports the continuing efforts of the research team.
Read more: New study on pathological mechanisms in ME from Bergen research group
The research team wishes to thank all 151 participants for their contributions to the RituxME trial. Thanks to their considerable efforts, the trial has furthered the ME/CFS research field, and the study data and biobank material may continue to yield new knowledge in the years to come.
The Kavli Trust has supported the ME/CFS research at Haukeland University Hospital since 2011. Read more here.
Top photo: Studies on biological mechanisms based on the RituxME trial are performed in close collaboration between the Dept. of Oncology at Haukeland University Hospital and Institute for Biomedicine at the University of Bergen. The research group represented by (from the left) Karl Johan Tronstad, Ina Pettersen, Kine Alme, Sissel Dyrstad, Ove Bruland, Kari Sørland and Olav Mella. Behind the camera: Molecular biologist Kristin Risa.